MET (also known as c-MET) is a receptor tyrosine kinase comprising a 50 kDa α-subunit and a 145 kDa β-subunit. The only known ligand for MET is hepatocyte growth factor (HGF), which is also known as scatter factor. Binding of HGF to MET leads to receptor dimerization and autophosphorylation of β-subunit residues Y1349 and Y1356, activating downstream signaling pathways that include the phosphoinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway, the signal transducer and activator of transcription factor (STAT) pathway, the mitogen-activated protein kinase (MAPK) pathway, and the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway. This ultimately leads to increased mitogenesis, cell proliferation, cell survival, and cell motility. Dysregulation of MET or HGF activity may occur, e.g., through overexpression, gene amplification, mutation, or alternative splicing of MET, or through HGF ligand-induced autocrine/paracrine loop signaling. Such dysregulation plays a role in many cancers by facilitating cancer invasiveness, angiogenesis, metastasis, and tumor growth, thus leading to a more aggressive cancer phenotype and a poorer prognosis.
MET is also known to interact with signaling pathways involving other receptors, such as EGFR, TGF-β, and HER3, and may play a role in resistance to treatments targeting those receptors. MET inhibitors, such as anti-MET antibodies, thus may be effective in combination with other receptor inhibitors in overcoming resistant phenotypes.
Current MET inhibitors include both monoclonal antibodies, which may target either MET or its ligand, HGF, and small molecule kinase inhibitors. Known antibodies targeting the MET pathway include the humanized anti-MET antibody onartuzumab (OA-5D5, OAM4558g, MetMAb); the humanized anti-HGF antibody ficlatuzumab (AV-299); the human anti-HGF antibody rilotumumab (AMG102); the humanized anti-HGF antibody TAK701; the humanized IgG4 anti-c-MET antibody LY2875358/LA480; the humanized anti-c-MET antibody ABT-700 (H224G11); and the ARGX-111 anti-c-MET antibody (36C4). Known anti-MET small molecule receptor tyrosine kinase inhibitors include tivantinib, cabozantinib, foretinib, golvatinib, and crizotinib. However, no anti-MET antibodies have been approved for therapeutic use.
In view of the critical role of MET in cancer progression, there is a need for new and improved therapies that target MET.